One of the goals of our lab is to use the olfactory system as a model to study the disruption and repair neural circuits within the central nervous system. To achieve this goal we first sought to establish the endogenous capacity of the olfactory system to re-establish proper wiring following broad disruption. We utilized the organization of the olfactory maps (both the glomerular map and intrabulbar map) as a framework to measure proper connectivity. Thus, in one study we over-expressed the apoptosis signaling protein, Fas- associated factor 1 (Faf1) in olfactory sensory neurons (OSNs) and revealed two main findings;1) that Faf1 does not directly induce apoptosis but rather causes axonal misrouting resulting in broad disorganization of the glomerular map, and 2) by shutting down Faf1 over-expression we show that the glomerular map can indeed restore its organization. These findings show that accurate connectivity can be re-established after the developmental process is complete (Cheng et al, J Neurosci. 2011). In related experiments we are studying the process of circuit disruption associated with neurodegeneration. In collaboration with Dr. Huaibin Cai at NIA we established an olfactory based model of disease related neurodegeneration. By expressing a mutant form of the Amyloid Precursor Protein (APP), linked to Alzheimers disease, in OSNs, we present three main findings;1) we show that neurodegeneration can be initiated very rapidly in the olfactory system (by 3 weeks of age), 2) we reveal that APP induces neural loss in a cell-autonomous manner suggesting that Amyloid plaques may not be the fundamental cause of neural loss, and 3) that blocking APP over-expression can rescue OSNs and reduce neural loss (Cheng et al., J Neurosci., 2011). We are currently in the process of examining the olfactory bulb circuitry in this mouse model to assess any organizational or functional disruption as well as determine the capacity for repair. Another goal of this project is to determine the role of the regenerating olfactory bulb interneurons on circuit plasticity and repair. For these experiments we are collaborating with the laboratory of Dr. Heather Cameron at NIMH by utilizing a transgenic approach to selectively eliminate neuroblasts that originate in from the subventricular zone (SVZ) and migrate to the bulb via the rostral migratory stream (RMS). Since these regenerating interneurons are the post-synaptic targets of intrabulbar projections that give rise to the intrabulbar map, they have direct bearing on map plasticity and restoration. Currently, we are assessing the circuitry of the olfactory bulb for deficits associated with eliminating these interneurons. Together these studies will help us understand the mechanisms that regulate circuit plasticity and repair in the olfactory bulb and possibly throughout the brain as well.